The transformation of a normal melanocyte into a melanoma requires factors above and beyond genetic mutations. We have identified lipids from subcutaneous adipocytes as one such contributing factor. When nascent melanoma cells come into contact with these adipocytes, they induce lipolysis and release of fatty acids into the extracellular space. These lipids are then directly taken up into the melanoma cell through FATP1 (Fatty Acid Transport Protein 1). Using a zebrafish model of melanoma coupled with validation in human tissues, we show that genetic and pharmacologic manipulation of FAPT1 interrupts the crosstalk between adipocytes and melanoma. Once inside the melanoma cell, these fatty acids undergo ?-oxidation and can fuel tumor proliferation and invasion programs. One end product of this metabolism is the production of acetyl-CoA, which we find can be used to modify histone acetylation within the melanoma cell and lead to widespread changes in gene expression. Despite the importance of the interaction between adipocytes and melanoma cells, it is unknown what signals mediate this cross-talk, or how these lipids are used by the melanoma cell to drive progression. In this proposal, we will take advantage of the complementary strengths of the zebrafish model and human cell culture models to elucidate these mechanisms. In Aim 1, we will test whether catecholamines secreted from melanoma cells, which occurs as a byproduct of melanin synthesis can induce lipolytic programs in the adipocytes. In Aim 2, we will use the rapid transgenic capabilities of the zebrafish to test whether adipocyte-specific knockout of the lipolytic enzyme ATGL abrogates melanoma growth and progression. This will be complemented using an ATGL knockout mouse melanoma model. Finally, in Aim 3 we will determine the mechanisms by which fatty acid derived acetyl-CoA modulates histone acetylation and melanoma cell behavior. These studies will highlight the way in which factors such as lipids from the microenvironment can reprogram tumor cells to enable malignant transformation. Identifying these mechanisms will provide new opportunities for therapeutic targeting of this cross-talk.